TNF Neutralization Results in the Delay of Transplantable Tumor Growth and Reduced MDSC Accumulation.

Kamar-Sulu N Atretkhany,Zhihai Qin,Sergei A Nedospasov,Ruslan V Zvartsev,Violetta S Gogoleva,Marina S Drutskaya,Maxim A Nosenko

doi:10.3389/fimmu.2016.00147

Abstract

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells (IMCs) that, under normal conditions, may differentiate into mature macrophages, granulocytes, and dendritic cells. However, under pathological conditions associated with inflammation, cancer, or infection, such differentiation is inhibited leading to IMC expansion. Under the influence of inflammatory cytokines, these cells become MDSCs, acquire immunosuppressive phenotype, and accumulate in the affected tissue, as well as in the periphery. Immune suppressive activity of MDSCs is partly due to upregulation of arginase 1, inducible nitric oxide synthase, and anti-inflammatory cytokines, such as IL-10 and TGF-β. These suppressive factors can enhance tumor growth by repressing T-cell-mediated anti-tumor responses. TNF is a critical factor for the induction, expansion, and suppressive activity of MDSCs. In this study, we evaluated the effects of systemic TNF ablation on tumor-induced expansion of MDSCs in vivo using TNF humanized (hTNF KI) mice. Both etanercept and infliximab treatments resulted in a delayed growth of MCA 205 fibrosarcoma in hTNF KI mice, significantly reduced tumor volume, and also resulted in less accumulated MDSCs in the blood 3 weeks after tumor cell inoculation. Thus, our study uncovers anti-tumor effects of systemic TNF ablation in vivo.

Highlights

Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous population of immature myeloid cells (IMCs) that instead of undergoing terminal differentiation start to expand under the influence of inflammation, cancer, or infection [1]
Using pharmacological inhibition of human TNF in humanized mice with either etanercept or infliximab, we demonstrated that in mice transplanted with MCA 205 fibrosarcoma, MDSC accumulation and tumor growth were significantly diminished
TNF is important for MDSC development, in turn, MDSCs play a crucial role in tumor progression [9, 35]

Summary

Introduction

Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous population of immature myeloid cells (IMCs) that instead of undergoing terminal differentiation start to expand under the influence of inflammation, cancer, or infection [1] These cells are characterized by co-expression of CD11b and Gr-1 and can be subdivided into two populations: granulocytic CD11b+Ly6G+Ly6Clow and monocytic CD11b+Ly6G−Ly6Chi cells [2]. Suppressive activity of MDSCs is associated with upregulation of arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), and anti-inflammatory cytokines, such as IL-10 and TGF-β [9, 13,14,15] These suppressive factors can enhance tumor growth by repressing T-cell proliferation as well as T-cell- and NK-cell-mediated anti-tumor responses [16,17,18,19]. MDSCs can attract other myeloid cells, such as neutrophils and macrophages, which further contribute to the inflammatory processes in tumor microenvironment [23]

Methods

Results

Conclusion